Abstract Background Congenital tuberculosis (TB) is uncommon and difficult to detect in neonates due to its nonspecific symptoms. We conducted a contact investigation of infants and healthcare workers (HCWs) exposed to a neonate with congenital TB in a neonatal ICU (NICU) in Korea. Methods A premature infant born was admitted to NICU on September 16, 2022. On October 24, the infant's mother was diagnosed with miliary TB, and infant’s sputum AFB stain showed 4 positive results. All NICU infants and HCWs during the same period were screened for active pulmonary TB using chest radiography (CXR) immediately. Exposed infants were evaluated with a TST and CXR three months after exposure. Interferon-Gamma Release Assay (IGRA) testing was performed on those with a positive TST or abnormal CXR finding. Prophylactic rifampin was provided to the exposed infants for 3 months, as index had isoniazid-resistant M. tuberculosis infection. Exposed HCWs underwent IGRA testing immediately after exposure (1st IGRA) and at 8 to 10 weeks post-exposure (2nd IGRA), and CXR was performed 6 months after exposure. Results Five out of 82 exposed infants had positive TST (≥ 10 mm) results, while all 31 infants who underwent IGRA testing had negative results. All five with positive TST had received BCG vaccination a median 105 days before. Of the 119 exposed HCWs, three had a conversion; two had negative results (on annual IGRA testing performed according to the national TB prevention Act) before exposure and positive at 1st IGRA test, and one had negative 1st IGRA test then positive 2nd IGRA test. None had active TB during 6-month follow-up. Conclusion We found that 6% of exposed infants had positive TST results and 0% had positive IGRA, while 2.5% of exposed HCWs had conversion. Considering the possibility of false positive TST results due to prior BCG vaccination, the chance of transmission to the infants would be 0%; otherwise, it would be 6.1%. Disclosures All Authors: No reported disclosures
Objective The neutrophil-to-lymphocyte ratio (NLR) is elevated in inflammatory diseases, but its clinical significance in systemic sclerosis (SSc) is unclear. This study evaluated NLR in diagnosing SSc and in predicting lung involvement such as interstitial lung disease (ILD). Methods The medical records of 88 patients with SSc and 50 healthy controls were reviewed. Exclusion criteria included active infection or the presence of any hematological, cardiovascular, or metabolic disorder. The NLR was compared between patients with SSc and healthy controls, and associations between NLR and lung involvement were analyzed. Results The NLR was significantly higher in patients with SSc compared to healthy controls (NLR, 3.95±6.59 vs. 2.00±1.07, p<0.01). Patients with SSc and ILD had higher NLR levels than those without ILD (p<0.01, p<0.05). NLR was negatively associated with forced vital capacity (r=−0.341, p<0.01), but not with diffusing capacity for carbon monoxide. Receiver-operating characteristics analysis of NLR to predict ILD in patients with SSc showed that the area under the curve was 0.763. The cut-off NLR value for prediction of lung involvement was determined to be 2.59 (sensitivity, 0.700; specificity, 0.729; p<0.01). Conclusion NLR may be a promising marker that reflects ILD in patients with SSc, and values greater than 2.59 were useful in predicting ILD.
Abstract In a recent study, a comprehensive library composed of 212 phantoms with different body sizes was established by deforming the adult male and female mesh-type reference computational phantoms (MRCPs) of ICRP Publication 145 and the next-generation ICRP reference phantoms over the current voxel-type reference phantoms of ICRP Publication 110. In this study, as an application of the MRCP-based phantom library, we investigated dosimetric impacts due to the different body sizes for neutron external exposures. A comprehensive dataset of organ/tissue dose coefficients (DCs) for idealized external neutron beams with four phantoms for each sex representatively selected from the phantom library were produced by performing Monte Carlo simulations using the Geant4 code. The body size-dependent DCs produced in this study were systematically analyzed, observing that the variation of the body weights overall played a more important role in organ/tissue dose calculations than the variation of the body heights. We also observed that the reference body-size DCs based on the MRCPs indeed significantly under- or overestimated the DCs produced using the phantoms, especially for those much heavier (male: 175 cm and 140 kg; female: 165 cm and 140 kg) than the reference body sizes (male: 176 cm and 73 kg; female: 163 cm and 60 kg) by up to 1.6 or 3.3 times, respectively. We believe that the use of the body size-dependent DCs, together with the reference body-size DCs, should be beneficial for more reliable organ/tissue dose estimates of individuals considering their body sizes rather than the most common conventional approach, i.e., the sole use of the reference body size DCs.
Introduction: Recently, robot thyroid surgery is performed worldwide in thyroid tumors1 and to reduce the surgical complication is also an important factor in robot surgery besides thyroidectomy.2–4 This video presents the surgical technique of preserving the recurrent laryngeal nerve and parathyroid gland in transaxillary robot thyroid surgery. Materials and Methods: Robot thyroid surgery has a problem of not knowing how strong the surgeon is holding and retracting the tissues or feel the thermal change when energy device is activated. Dissection or manipulation should be performed by layers and structures. The surgeon should not advance to the next procedure immediately after activating the coagulating energy device when related to tissues for preservation since there could be a thermal injury. After the activation, pause or make contact to a gauze placed in the operative field to check the spread of remaining heat. The shielded side of the device should be placed to the remnant structure side. By doing so, the thermal spread could be minimized. When coagulating vessels, surgeon should not impatiently manipulate the grasped tissues since it could tear before fully coagulated and encounter bleeding. When preserving the recurrent laryngeal nerve and parathyroid gland, these surgical tips are very important to minimize the injury. Results: By applying such surgical techniques, the result of preserving the recurrent laryngeal nerve and parathyroid gland is safe and secure in robot thyroid surgery5 as presented in our video. Conclusion: Endocrine surgeons are to perform functionally safe thyroidectomy and reduce the surgical complications in any types of thyroid surgery. Above-mentioned techniques will help preserve the recurrent laryngeal nerve and parathyroid gland in robot thyroid surgery. No competing financial interests exist. Runtime of video: 4 mins 57 secs
Abstract The continued advancement of targeted therapies for actionable gene rearrangements has increased the demand for cost-effective screening methods for detecting these gene rearrangements in papillary thyroid carcinoma (PTC). Herein, ribonucleic acid (RNA) sequencing was performed on 106 patients with PTC having wild-type BRAF. The patients were divided into two groups: Group 1 (n = 58) included patients selected by an endocrine pathologist based on characteristic pathological features, including multinodular invasive growth, prominent intratumoral stromal fibrosis, mixed-growth patterns with varying degrees of nuclear atypia, pale eosinophilic to clear cytoplasm, and/or multiple lymph node (LN) metastasis. These patients were prescreened and then subjected to pan-tyrosine receptor kinase (TRK) immunohistochemistry (IHC) staining and RNA sequencing. In Group 2, RNA sequencing was conducted on samples from 48 randomly selected patients. Gene rearrangements were identified in 66 patients (62.3%), with a significantly higher proportion in Group 1 (77.6%) than in Group 2 (43.8%) (p < 0.001). NTRK was the most common gene rearrangement, which was detected in 31 patients (29.2%). The second most common gene rearrangement was RET (18.9%), followed by ALK (9.4%), and then BRAF (2.8%). Patients with gene rearrangements were significantly younger and had smaller primary tumors, although they demonstrated greater extrathyroidal extension and LN metastasis than those without rearrangements. Pan-TRK IHC revealed a sensitivity of 52% and a specificity of 94% for the prediction of NTRK gene rearrangements. This study demonstrates that pathological screening combined with pan-TRK IHC is a cost-effective method for examining targetable gene rearrangements in patients with PTC having wild-type BRAF.
The dynamic risk stratification (DRS) and its current definition of each response-to-therapy category in postlobectomy papillary thyroid carcinoma (PTC) patients have not been well studied. This study aimed to validate the DRS system and to investigate useful thyroglobulin (Tg) or anti-Tg antibody (Ab)-related parameters in defining each response-to-therapy category. This historical cohort study included 619 patients with PTC treated by thyroid lobectomy. All enrolled participants were stratified according to the American Thyroid Association (ATA) initial risk stratification system and DRS system, respectively. The association between these stratifications and structural recurrence was evaluated.
Immunotoxins consisting of a toxin from bacteria or plants and a targeting module have been developed as potent anti-cancer therapeutics. The majority of them, especially those in preclinical or clinical testing stages, are fusion proteins of a toxin and antibody fragment. Immunotoxins based on full-length antibodies are less studied, even though the fragment crystallizable (Fc) domain plays an important role in regulating the concentration of immunoglobulin G (IgG) in the serum and in antibody-mediated immune responses against pathogens.We devised a method to site-specifically conjugate IgG and another protein using a cysteine residue introduced into the IgG and a bio-orthogonally reactive unnatural amino acid incorporated into the other protein. The human epidermal growth factor receptor 2 (Her2)-targeting IgG, trastuzumab, was engineered to have an unpaired cysteine in the heavy chain, and an unnatural amino acid with the azido group was incorporated into an engineered Pseudomonas exotoxin A (PE24). The two protein molecules were conjugated site-specifically using a bifunctional linker having dibenzocyclooctyne and maleimide groups. Binding to Her2 and interaction with various Fc receptors of trastuzumab were not affected by the conjugation with PE24. The trastuzumab-PE24 conjugate was cytotoxic to Her2-overexpressing cell lines, which involved the inhibition of cellular protein synthesis due to the modification of elongation factor-2.We constructed the site-specifically conjugated immunotoxin based on IgG and PE24, which induced target-specific cytotoxicity. To evaluate the molecule as a cancer therapeutic, animal studies are planned to assess tumor regression, half-life in blood, and in vivo immunogenicity. In addition, we expect that the site-specific conjugation method can be used to develop other antibody-protein conjugates for applications in therapeutics and diagnostics.
Regulating protein import across the endoplasmic reticulum (ER) membrane occasionally results in the synthesis of topologically unnatural variants, and their accumulation often leads to proteotoxicity. However, since this is a regulated process, it is questionable whether the topological rearrangement really has adverse consequences. In the present study, we provide an insight into the functional benefit of translocational regulation by illustrating mutant-selective topologic conversion (MSTC) and demonstrate that MSTC contributes to selective degradation of a membrane-anchored prion protein isoform (ctmPrP). We find that ctmPrP is inherently short-lived and topologically competent for degradation rather than accumulation. MSTC achieves, cotranslationally, the unique topology of ctmPrP during translocation, facilitating selective ctmPrP degradation from the ER via the proteasome-dependent pathway before entering the secretory pathway. At this time, the N-terminal polycationic cluster is essential for MSTC, and its cytosolic exposure acquires "ERAD-degron"-like activity for ctmPrP. Bypassing MSTC delays ctmPrP degradation, thus increasing prion proteotoxicity. Thus, topological rearrangement is used for the MSTC as a part of the protein quality control pathway to ensure the safety of the secretory pathway from misfolded PrP.
Phosphodiesterase-5 inhibitors (PDE5i) have been developed for the treatment of coronary artery disease, but they are now widely used for the treatment of erectile dysfunction. Unfortunately, these drugs are also known to cause several ocular side effects. Among those symptoms that may be experienced, a nonarteritic anterior ischemic optic neuropathy (NAION) is the most common neuro-ophthalmological complication, and the prevalence is 0.09%–0.18% (1). To date, an occurrence of a fourth cranial nerve palsy has not been reported in the literature. The authors report a fourth cranial nerve palsy after sildenafil administration in a patient. A 50-year-old previously healthy man was referred to our clinic with a presumed diagnosis of a left fourth cranial nerve palsy. The patient developed an acute diplopia on his down gaze 20 days ago. He had a medical history of a right facial palsy that occurred 12 years ago and it recovered spontaneously, and there was no significant medical history such as diabetes mellitus, hypertension, hyperlipidemia, or cardiovascular disorder, excepting an erectile disorder. There was no significant surgical history or social history such as tobacco use. He denied any trauma history. The only medication that the patient was taking at that time was sildenafil. The day before the onset of the diplopia, he had taken sildenafil at 50 mg for erectile dysfunction. On review of the system, there were no other symptoms except that he experienced a flushing sensation and a headache right after the intake of sildenafil, which was noted as having been 1 day before the onset of the experience of diplopia, according to the patient's statement. On ocular examination, his visual acuity was noted as having been 20/20 in both eyes, and the measured intraocular pressure was normal range in both eyes. The distance and near deviation angles at that time were both orthotropia. A left hypertropia of 8 prism diopters (PDs) was measured in down gaze, and a 2 PD of left hypertropia was measured on dextroversion. The patient was orthophoric on other gazes. On the Bielschowsky head tilt test, the patient was orthophoric on a right head tilt and showed a 8 PD of the left hypertropia on a left head tilt. On the extraocular motility test, it was considered as notable for full ductions of his right eye, but 75% of the normal superior oblique muscle function was observed in the left eye. Both of the patient's pupils reacted normally to the direct light, and no disability in the afferent pupillary reaction was observed. The anterior segment examination showed normal findings, and the fundus examination revealed a healthy appearing optic nerve with 0.3 cup-to-disc ratio in both eyes, a mild excyclotorsion in the left eye, and otherwise unremarkable findings in both eyes of the retina. Upon review of a performed high-resolution pre- and post-contrast cranial nerve MRI with 3-dimensional sequences using a 3-T system (Magnetom Skyra; Siemens Healthineers, Erlangen, Germany) with a 32-channel phased-array head coil, this test revealed no abnormality in fourth cranial nerve pathway, and no abnormality was found on an MRA. Laboratory tests showed a hemoglobin level of 15.8 g/dL, white blood cell count of 5.32 × 103 μL (segmented neutrophil 58.8%, lymphocyte 36.3%, and monocyte 3.4%), and normal electrolytes. The erythrocyte sedimentation rate and C-reactive protein levels were noted also to be as normal. The fasting blood glucose level was noted as 96 mg/dL. Under this circumstance, the serological investigations revealed a positive result of antinuclear antibody, whereas the patient's anti-neutrophil cytoplasmic antibody showed a negative result. The anticardiolipin antibody, ganglioside antibody, thyroid antibody, and acetylcholine receptor antibody were all noted to have been within normal range. Other tests—liver, renal, and coagulation panel—were also noted as being normal. Although the antinuclear antibody showed positive findings, there were no symptoms representing rheumatic diseases such as dry eye, dry mouth, ulcer, and arthritis. Based on the above results, the patient was diagnosed as sildenafil-associated left fourth cranial nerve palsy. By preventing the cyclic guanosine monophosphates (cGMP) degradation, PDE5i enhance the vascular smooth muscle relaxation. In addition, since nitric oxide (NO) is required for cGMP to be produced, the PDE5i amplify the role of NO donors by interfering with cGMP degradation (2). Therefore, patients with cardiovascular disease who take nitrates should be cautious when taking sildenafil together because there may be serious side effects along with severe hypotension, and some of these side effects may even result in the death of the patient if left untreated (3). The incidence of cranial nerve palsy after the administration of sildenafil is very rare to occur in a patient, and only a few cases have been reported. Oculomotor nerve palsy (4) and the case of a combined oculomotor nerve palsy and abducens nerve palsy (5) have been reported in 1 case each. According to the previous case reports, preceded by headache, the diplopia appeared within 1 hour to 1 day after taking the medicine, whereby the condition shown to have improved within 3 months (4,5). In our case, the patient felt a headache immediately after taking sildenafil. The next day, diplopia caused by a fourth nerve palsy had developed. In all 3 cases, including our case, an acute cranial nerve palsy occurred within 1 day after taking sildenafil-based drugs, but the likelihood of temporal coincidence cannot be excluded as Donahue et al (4) mentioned. PDE5i also have been reported to increase the risk of NAION, which is caused by ischemia of the optic nerve head. It is known that PDE5 is widely expressed in the corpora cavernosa of penis, systemic arteries and veins, the pulmonary arteries, the myocardium, the skeletal muscles, and in the platelets, and the PDE5i can cause hypotension. Our case along with previously reported cases suggests that PDE5i can induce neurologic dysfunction probably related with systemic hypotension, even in patients without concomitant intake of nitrates (4). In conclusion, we report a case of fourth cranial nerve palsy a day after sildenafil administration. When treating patients with fourth nerve palsy, PDE5i may need to be scrutinized because the patients themselves may be reluctant to speak on these issues and PDE5i may be able to interact with underlying diseases or other drugs that it was taken.
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